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					                      Alcohol and Endocrinology (Rivier)




             Alcohol and Endocrinology



                  Lecturer: Catherine Rivier, Ph.D.
                                   The Salk Institute
                                   The Clayton Foundation Laboratories
                                   for Peptide Biology
                                   La Jolla, CA, USA



                   Editor: Joanne Weinberg, Ph.D.
                                   Department of Anatomy
                                   Faculty of Medicine
                                   University of British Columbia
                                   Vancouver, CANADA




Supported by: NIH Grants NIAAA 08924 and NIAAA 06420.




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                           Alcohol and Endocrinology (Rivier)




                        ORGANIZATION OF THE TALK

•   General overview of endocrine systems: What functions do they serve?

•   Influence of alcohol on endocrine systems: General mechanisms.

•   The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal
    (HPG) axes.




     ENDOCRINOLOGY AND THE PRINCIPLE OF HOMEOSTASIS

An essential aspect of mammalian organisms is that their cells must communicate with
each other. They do so via nerve impulses and blood-borne signals. Endocrinology is
concerned with the study of these blood-borne, chemical messengers (hormones),
substances secreted by cells of endocrine glands and tissues, that regulate the activity of
other cells in the body.

Role of hormones:
For the body to function properly, its various parts and organs must communicate with
each other in order to:

1. Ensure that a constant internal environment (i.e., homeostasis) is maintained.

2. Enable the organism to respond appropriately to any changes in their internal or
   external environment.

The capacity of specialized tissues to function in this integrated fashion is made
possible by two control mechanisms that are functionally linked:

1. The nervous system, which transmits electrochemical signals as two-way traffic
   between the brain and peripheral tissues, or between tissues in reflex circuits. Can
   be viewed as a wired system.

2. The endocrine system, which releases chemical mediators called hormones into the
   circulation and/or to adjacent tissues. Can be viewed as a wireless system.

Endocrinology has been defined as the branch of biological science that concerns itself
with the actions of hormones and the organs in which the hormones are formed.


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                          Alcohol and Endocrinology (Rivier)



                               ENDOCRINE GLANDS


Endocrine glands (ductless glands) are specialized organs that manufacture hormones
and secrete them directly into the blood stream. This is in contrast to exocrine glands
such as salivary glands, which release their products into ducts leading into the lumen
of other organs (such as the intestine).

Main endocrine glands                                  Hormones
pituitary gland (hypophysis)                    ACTH, TSH, LH, FSH, GH, PRL
adrenals                                        corticosteroids
thyroid                                         thyroxine (T4), triiodothyronine (T3)
parathyroid                                     parathyroid hormone
gonads (testes and ovaries)                     testosterone, estrogen, progesterone
pineal                                          melatonin
pancreas                                        insulin, glucagon, somatostatin, etc.
gastrointestinal tract                          gastrin, cholecystokinin, motilin, etc.




                          FUNCTION OF HORMONES

•   Reproduction
•   Growth and development
•   Maintenance of internal environment (electrolytic content of body fluids, blood
    pressure and heart rate, acid-base balance, temperature, etc.)
•   Physiological response to stressors
•   Energy production, utilization and storage




                    CHEMICAL NATURE OF HORMONES

•   Peptides and amino acid derivatives
       - Glycoproteins (TSH, LH, FSH)
       - Peptides (ACTH)
       - Sugarless proteins (insulin)

•   Derivatives of single amino acids (catecholamines, serotonin, histamine)

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                           Alcohol and Endocrinology (Rivier)



•   Steroids (adrenal, gonadal, brain)


                              THE HYPOTHALAMUS

Slide 1 illustrates a sagital view of the human brain. The hypothalamus is the basal part
of the diencephalon lying below the thalamus, as its name implies. It forms the walls
and lower part of the third ventricle of the brain. The endocrine hypothalamus is
connected to and influenced by the rest of the central nervous system by synaptic
contacts from other neuronal elements. Information flows from other brain centers and
is relayed to the hypothalamus through pathways that manufacture neurotransmitters
such as catecholamines, serotonin, etc. This is how information from the periphery is
coded and conveyed to the hypothalamus, allowing this structure to mount appropriate
endocrine responses aimed at restoring homeostasis.




                                                Slide 1


                  THE HYPOTHALAMIC-PITUITARY AXIS

Type                                                           Major Role
HYPOTHALAMIC HORMONES
Corticotropin-releasing factor (CRF)                       ACTH
Gonadotropin-releasing hormone (GnRH)                      LH (FSH)
Growth hormone releasing hormone (GHRH)                    GH
Somatotropin release inhibiting hormone                    GH
(Somatostatin)
TSH-releasing hormone (TRH)                                TSH

ANTERIOR PITUITARY HORMONES


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                          Alcohol and Endocrinology (Rivier)


Adrenocorticotropin (ACTH)                           adrenal steroidogenesis
LH, FSH (gonadotropins)                              gonadal steroidogenesis
Prolactin                                            milk synthesis
Growth hormone                                        alters metabolic processes
Thyroid stimulating hormone (TSH)                    thyroid hormones synthesis



        INFLUENCE OF ALCOHOL ON ENDOCRINE SYSTEMS:
                   GENERAL MECHANISMS

Alcohol could act by influencing:

•   Hormone synthesis, storage and release
•   Hormone transport:
      For water-soluble molecules, transport in plasma without specific transport
      mechanisms
      For more insoluble hormones: carrier mechanisms (transport proteins; because
      only free, unbound hormones enter cells, these proteins act as reservoirs)
•   Hormone regulation by feedback mechanisms
•   Hormone mechanisms of action: Interaction with receptors, effect on second
    messengers


                 THE HYPOTHALAMIC-PITUITARY AXIS




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    Alcohol and Endocrinology (Rivier)



                              Slides 2 and 3:
                              Neurons of the hypothalamus
                              that synthesize CRF and
                              vasopressin are found in an area
                              called the paraventricular
                              nucleus (PVN). These cell bodies
                              send axons to the median
                              eminence, where peptides are
                              released from the nerve terminals
                              and are transported through
                              vessels of the portal system When
                              they reach the anterior pituitary,
                              these peptides act on their
                              respective receptors, thereby
                              stimulating ACTH secretion.
                              (Rivier, C. 1996 Alcoholism: Clin.
                              Exper. Res., 20:240-254)




                              Slide 2


THE HYPOTHALAMIC-PITUITARY AXIS




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                         Alcohol and Endocrinology (Rivier)


      Anatomy of the Pituitary Gland
SUPERIOR                     HYPOTHALAMUS
HYPOPHYSI AL
ARTERY




                               PORTAL VEINS


       ACTH
                                                  Slide 3




Slide 4: Following its release into the
general circulation, ACTH acts on the
cortex of the adrenal glands, which
manufacture and secrete glucocorticoids
(corticosterone in rodents and cortisol
in humans). These glucocorticoids exert
a classical negative feedback influence
on the pituitary, where they inhibit the
effect of CRF and VP, and on the PVN,
where they inhibit the synthesis of CRF.
Thus after a stimulus induces CRF and
ACTH release, the production of
glucocorticoids will eventually
terminate this release, thereby ensuring
the maintenance of homeostasis.




           IMPORTANCE OF CRF AND GLUCOCORTICOIDS


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                            Alcohol and Endocrinology (Rivier)


                                FOR HOMEOSTASIS




                                                              Slide 5




                  Slide 6


Both CRF and steroids produced by the adrenal gland (glucocorticoids) exert a plethora
of effects within the body. The most important effects are illustrated on Slides 5 and 6.
These wide-ranging effects underscore the importance of understanding how the HPA
axis functions, what effects various stimuli exert on it, and the mechanisms through
which there effects are exerted.


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                             Alcohol and Endocrinology (Rivier)



                     EFFECT OF ALCOHOL ON THE
                HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

These studies were done to investigate the effect of alcohol on ACTH release, and the
relationship between the amount of alcohol injected and this hormone response.

                                                      Slide 7 illustrates the time course of the
                                                      ACTH response to the intraperitoneal
  pg ACTH/ ml                                         (ip) injection of two different doses of
     1000                                             alcohol to intact male rats. This
      900
                                  vehicle             response was dose-dependent in that
      800                         EtOH 1 g/kg         the larger alcohol dose induced the
      700                         EtOH 3 g/kg         larger release of ACTH. It was also
      600
                                                      time-dependent in that the ACTH
                                                      response was longest in response to the
      500
                                                      larger dose of alcohol. Comparable
      400                                             results can be obtained when alcohol is
      300                                             infused into the stomach (ig), which is a
      200                                             route more comparable to that used by
      100                                             humans. Each point represents the
        0                                             mean + SEM of 5-6 animals. **, P < 0.01
            0 10 30   60         120        180       versus vehicle (bottom line).
                        time (min)                    (Modified from: Ogilvie KM, Lee S,
                                                      Rivier C. 1997 Alcoholism: Clin. Exper.
                                                      Res. 21:467-476, Blackwell Publishing.)




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                           Alcohol and Endocrinology (Rivier)




Slide 8 illustrates the relationship
between ACTH release and blood alcohol
levels (BALs) following the ip or ig
injection of alcohol. ACTH data represent
cumulative hormone release over a 60
min time period. BALs data illustrate
peak values for each dose. Each bar
represents the mean + SEM of 5-6
animals. *, P < 0.05 and **, P < 0.01 versus
vehicle (“0” alcohol). (Modified from:
Ogilvie KM, Lee S, Rivier C. 1997
Alcoholism: Clin. Exper. Res. 21:467-476,
Blackwell Publishing.)


These results were obtained in rats to which alcohol was administered through an
investigator-controlled process. However, we recently observed that rats that self-
administer the drug also display activation of their HPA axis. Similarly, alcohol can
stimulate the HPA axis of humans. Results obtained following a single drink are
variable, and some investigators believe that this treatment does not release
ACTH/cortisol unless alcohol induces gastrointestinal discomfort. In contrast,
alcoholics usually show evidence for persistently deregulated HPA axis activity, as
illustrated, for example, by altered pituitary responsiveness to challenges and the
occurrence of pseudo-Cushing's syndrome (truncal obesity, moon face, easy
bruisability, etc.).

Alcohol could act at the level of:
- PVN afferents
- PVN itself (secretagogues synthesis and release; responsiveness to neurotransmitters)
- Median eminence (secretagogues release, effect of neurotransmitters)
- Pituitary (receptors, second messengers, intracellular molecular mechanisms)
- Adrenals (including events related to steroid feedback)

• Hypothalamus: Alcohol stimulates CRF synthesis.
These experiments were done to investigate the PVN neuronal response to the ip
injection of alcohol (3 g/kg).



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                               Alcohol and Endocrinology (Rivier)




Slide 9                                             Slide 10

Slide 9 depicts a rat brain and the site along which the brain was cut. This cut is called
coronal, and indicates that it was made along longitudinal section passing through the
brain at right angles to the median plane.

Slide 10 illustrates pictures of a coronal section of the rat PVN. The left side illustrates a
cartoon of this nucleus while the right side shows a section of this nucleus stained to
show landmark anatomical features. The third ventricle (3V) is in the middle and the
PVN is situated on each side, in the shape of the wings of a butterfly. Several areas of
the PVN are also illustrated, including the parvocellular (pc) portion, which contains
CRF and VP neurons with terminals in the median eminence, and the magnocellular
(MC) portion, which contains VP but no CRF neurons.

                                                Slide 11 illustrates the ability of alcohol to
                                                stimulate CRF and VP synthesis, as shown
                                                by increases in CRF and VP heteronuclear
    Veh icle            Veh icle
                                                RNA levels in neurons of the PVN. Peak
                                                CRF and VP responses, which are
                                                illustrated here, were measured 20 and 5
                 PV N
                                                min after alcohol treatment.
    EtOH                EtOH


               CRF                 VP

The question therefore was, does alcohol release ACTH by stimulating CRF and VP
secretion, or does it (also?) act directly on the pituitary? We conducted the following
experiments in order to answer this question.

• Alcohol does not act directly on the pituitary.
In order determine whether alcohol could stimulate the pituitary directly (i.e. without
CRF or VP), we first measured the ACTH response to the injection of alcohol into the

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                          Alcohol and Endocrinology (Rivier)


brain ventricle (Slide 12). While the dose we used did not cause the appearance of the
drug in the general circulation, it remained possible that it reached the pituitary.
Consequently, while these results are very informative, they do not provide a definite
answer.




Slide 12. Effect of the icv injection of
alcohol (5 l) on ACTH release. Each
point corresponds to the mean + SEM of 5-
6 rats. **, P < 0.01.




• Role of CRF and VP in modulating the ACTH response to alcohol.
As alcohol induces the release of CRF and VP, we then asked whether these peptides
modulate the ACTH response to alcohol. To test this hypothesis, we measured plasma
ACTH levels in rats injected with antibodies that immunoneutralize endogenous CRF
and VP, or with antagonists to their receptors.
In Slide 13, groups of rats administered alcohol were previously (-1 h) injected with
antibodies (ab) that immunoneutralized CRF or VP. These studies indicate that
removal of endogenous CRF reduced the ACTH response by >85% while removal of
endogenous VP produced a significant, but less potent effect. Removal of both peptides
totally abolished the ACTH response. We conclude from these data as well as those of
others, that endogenous CRF is a central mediator of the ACTH response to alcohol
while VP only partially mediates it.




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                            Alcohol and Endocrinology (Rivier)




                                                Slide 13. Each bar represents the mean +
                                                SEM of 5-7 animals. *, P<0.05 and **,
                                                P<0.01 vs. corresponding vehicle.




Finally, we measured the response of the pituitary pro-opiomelanocortin (POMC) to
alcohol injection in the presence or absence of endogenous CRF and VP. While both the
systemic and the icv injection of alcohol elicited a significant response,
immunoneutralization of both CRF and VP completely abolished these responses (Slide
14). These results indicate that CRF and VP are necessary for the stimulatory influence
of alcohol on the pituitary corticotrophs.

A                                              B




Slide 14. The stimulatory effect of alcohol (ip, 3.0 g/kg, left panel, or icv, 5 l, right
panel) on pituitary POMC levels is abolished when endogenous CRF and VP are
immunoneutralized. Each bar represents the mean + SEM of 5-6 rats. *, P<0.05; **,
P<0.01.
• Effect of prior exposure to alcohol.
In general, exposure to a stimulus alters the ability of the HPA axis to subsequently
respond to this same stimulus or different stimuli. Accordingly, prior exposure to
alcohol modifies the response of the HPA axis to subsequent challenges.



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                          Alcohol and Endocrinology (Rivier)




In Slide 15, rats were injected
with the vehicle or alcohol
(2.0 g/kg, ip) 3 h prior to
being exposed to a neurogenic
stressor (mild
electrofootshocks). Alcohol-
pretreated rats showed a
significantly lower ACTH
response to shocks. Each
point represents the mean +
SEM of 6 rats. **, P<0.01 vs.
prior treatment with vehicle.




                                                  In Slide 16, rats were exposed to
                                                  alcohol vapors (4 h/day) for 3
                                                  consecutive days. On the 4th day,
                                                  they were injected with the immune
                                                  stimulus lipopolysaccharide (LPS, 2
                                                  g/kg, iv). Plasma ACTH levels are
                                                  illustrated as mean + SEM, N = 5-6.
                                                  **, P < 0.01.




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                          Alcohol and Endocrinology (Rivier)




Slide 17. Influence of prior exposure to alcohol (3.0 g/kg, ig, -7/10 d) on the ACTH
response to a second alcohol challenge (4.5 g/kg, ig). Each bar represents the mean +
SEM of 5-6 rats. (Copyright 1997 by the Society for Neuroscience; Lee and Rivier; J.
Neurosci. 1997; 17(22):8856-8866.)

We also showed that even when alcohol was administered as little as 3 days or as much
as 3 weeks before by the gastric (g) route, significantly decreases the HPA axis response
to a second alcohol challenge. Slide 17 illustrates the influence of alcohol injected 7
days earlier.

Left Panel: Rats exposed to 3 consecutive alcohol injections (4.5 g/kg, ig) 7 days earlier
exhibit a significantly decreased ACTH response to a second alcohol injection (4.5 g/kg,
ig). The ACTH response is illustrated as cumulative pg/ml measured 15, 30 and 45 min
after alcohol injection. Each bar represents the mean + SEM of 5-6 rats. xx, P < 0.01.

Right Panel: Neuronal response in the hypothalamic PVN to an alcohol challenge (4.5
k/kg, ig) delivered to control rats or rats exposed to alcohol 7 days earlier. Signals
represent mRNA levels of the immediate early gene NGFI-B, measured by in situ
hybridization.

While we only illustrate here results obtained in our own laboratory, other investigators
have reported comparable findings. For example, rats that self-administered alcohol for
several weeks displayed changes in HPA axis activity that persisted for at least 3 weeks
after cessation of drug exposure. Similarly, people who were alcohol-dependent
showed persistent hyporeactivity of their HPA axis.

Because of the multi-facetted influence of the hormones of the HPA axis (CRF, POMC,
adrenal steroids), alcohol-induced changes in this axis have far-reaching consequences
for the health of the organism. In other words, our results and those of others suggest

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                          Alcohol and Endocrinology (Rivier)


that an animal or a human being that has been exposed to alcohol recently cannot
mount an appropriate HPA axis response to a different stressor.
Collectively, these results indicate that alcohol exerts long-term consequences on the
HPA axis, which becomes refractory to additional drug challenges. It is possible that
the inability of an animal or a person to mount a normal HPA axis response to a second
alcohol challenge plays a role in alcohol abuse. According to this hypothesis, an animal
would increase its drug intake in order to regain the original HPA axis response to
alcohol.

•       Long-term consequences of alcohol exposure.
We have seen earlier that CRF and glucocorticoids have widespread effects. Here we
illustrate in cartoon form a few of the consequences of an hypoactive (right panel) or
hyperactive (left panel) HPA axis. This can result from, respectively, prolonged
postnatal treatment with alcohol (right panel) or exposure to alcohol during embryonic
development (left panel) which is not discussed here but is presented in, for example,
Lee et al. 2000, 2003, as well as Osborn et al., 2000 and Gabriel et al., 2001, 2005.

These studies have important translational consequences because they provide insight
into the mechanisms through which alcohol impairs a person's ability to adequately
respond to other stressors. As we have seen, the HPA axis is central to the organism's
ability to restore and maintain homeostasis, and when this ability is compromised
because endocrine responses become inadequate, various pathologies can take place
(including, for example, inadequate immune responses that may result in inflammation
oir infection). These experiments are also starting to shed light onto the endocrine
mechanisms that may participate in alcohol abuse, in as much as a person may increase
his/her alcohol intake in an attempt to restore the original HPA axis response to the
drug. Finally, another influence of an hyperactive HPA axis is inhibition of
reproductive functions, which is examined in the following section.




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                          Alcohol and Endocrinology (Rivier)




                                                       Slide 18.
References

S. Hiller-Sturmhöffel and A. Bartke. The endocrine system : An overview. Alcohol
Health and Research World 22: 153-164, 1998.

C. Rivier. Alcohol stimulates ACTH secretion in the rat: Mechanisms of action and
interactions with other stimuli. Alcoholism: Clin Exper Res. 20: 240-254, 1996.

C. Rivier and S. Lee. Acute alcohol administration stimulates the activity of
hypothalamic neurons that express corticotropin-releasing factor and vasopressin. Brain
Res 726:1-10, 1996.

S. Lee and C. Rivier. An initial, three-day long treatment with alcohol, induces a long-
lasting phenomenon of selective tolerance in the activity of the rat hypothalamic-
pituitary-adrenal axis. J Neurosci 17:8856-8866. 1997.

C. Rivier. Alcohol rapidly lowers plasma testosterone levels in the rat: Evidence that a
neural brain-gonadal pathway may be important for decreased testicular
responsiveness to gonadotropin. Alcoholism: Clin Exper Res 23:38-45, 1999.

S. Lee, D. Schmidt, F. Tilders, M. Cole, A. Smith and C. Rivier. Prolonged exposure to
intermittent alcohol vapors blunts hypothalamic responsiveness to immune and non-


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                           Alcohol and Endocrinology (Rivier)


immune signals. Alcoholism: Clin Exper Res 24:110-122, 2000.

S. Lee, D. Schmidt, F. Tilders and C Rivier. Increased activity of the hypothalamic-
pituitary-adrenal axis of rats exposed to alcohol in utero: Role of altered pituitary and
hypothalamic function. Mol Cell Neurosci 16:515-528, 2000.

S. Lee, D. Schmidt, F. Tilders and C. Rivier. Effect of repeated exposure to alcohol on the
response of the hypothalamic-pituitary adrenal axis of the rat: I. Role of changes in
hypothalamic neuronal activity. Alcoholism: Clin Exper Res 25:98-105, 2001.

S. Lee and C. Rivier. Long-term influence of an initial exposure to alcohol on the rat
hypothalamic-pituitary axis. Alcoholism: Clin Exper Res 27:1463-1470, 2003.

C. Rivier, D. Grigoriadis and J. Rivier. Role of corticotropin-releasing factor receptors
type 1 and 2 in modulating the rat ACTH response to stressors. Endocrinology
144:2396-2403, 2003.

S. Lee, C.A. Blanton and C. Rivier. Prenatal ethanol exposure alters responsiveness of
the rat hypothalamic-pituitary-adrenal axis to nitric oxide. Alcoholism: Clin Exper Res
27:962-969, 2003.

S. Lee, D. Selvage and C. Rivier. Site of action of acute alcohol administration in
stimulating the rat hypothalamic-pituitary-adrenal axis: Comparison between the effect
of systemic and intracerebroventricular injection of this drug on pituitary and
hypothalamic responses. Endocrinology 145:4470-4479, 2004.

R.G. Veldman and A.E. Meinders. On the mechanism of alcohol-induced pseudo-
Cushing's syndrome. Endocr Rev 17:262-268, 1996.

C. Waltman, L.S. Blevins, Jr., G. Boyd and G.S. Wand. The effects of mild ethanol
intoxication on the hypothalamic-pituitary-adrenal axis in nonalcoholic men. J Clin
Endocrinol Metab 77:518-522, 1993.

G.S. Wand and A.S. Dobs. Alterations in the hypothalamic-pituitary-adrenal axis in
actively drinking alcoholics. J Clin Endocrinol Metab 72:1290-1295, 1991.

C. Gianoulakis, X. Dai and T. Brown. Effect of Chronic Alcohol Consumption on the
Activity of the Hypothalamic-Pituitary-Adrenal Axis and Pituitary beta-Endorphin as a
Function of Alcohol Intake, Age, and Gender. Alcoholism: Clin Exper Res 27:410-423,
2003.

W.J. Inder, P.R. Joyce, J.E. Wells, M.J. Evans, M.J. Ellis, L. Mattioli and R.A. Donald. The
acute effects of oral ethanol on the hypothalamic-pituitary-adrenal axis in normal
human subjects. Clin Endocrinol 42:65-71, 1995.

H. Ehrenreich, J. Schuck, N. Stender, J. Pilz, O. Gefeller, L. Schilling, W. Poser and S.
Kaw. Endocrine and hemodynamic effects of stress versus systemic CRF in alcoholics

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during early and medium term abstinence. Alcoholism: Clin Exper Res 21:1285-1293,
1997.

W.R. Lovallo, S.L. Dickensheets, D.A. Myers, T.L. Thomas and S.J. Nixon. Blunted stress
cortisol response in abstinent alcoholic and polysubstance-abusing men. Alcoholism:
Clin Exper Res 24:651-658, 2000.

D.D. Rasmussen, B.M. Boldt, C.A. Bryant, D.R. Mitton, S.A. Larsen and C.W. Wilkinson.
Chronic daily ethanol and withdrawal: 1. Long-term changes in the hypothalamo-
pituitary-adrenal axis. Alcoholism: Clin Exper Res 24:1836-1849, 2000.

J.A. Osborn, C. Yu, G.E. Stelzl and J. Weinberg. Effects of fetal ethanol exposure on
pituitary-adrenal sensitivity to secretagogues. Alcohol Clin Exper Res 24:1110-9, 2000.

K.I. Gabriel, L. Ellis, W. Yu and J. Weinberg. Variations in corticosterone feedback do
not reveal differences in hpa activity after prenatal ethanol exposure. Alcohol Clin
Exper Res 25:907-15, 2001.

K.I. Gabriel, M.M. Glavas, L. Ellis and J. Weinberg. Postnatal handling does not
normalize hypothalamic corticotropin-releasing factor mRNA levels in animals
prenatally exposed to ethanol. Brain Res Dev Brain Res 157:74-82, 2005.




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                                Alcohol and Endocrinology (Rivier)

            THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS




                  L HRH




                     LH & FSH




                 Ovary            Testis


  estradiol
  progesterone   ovum     sperm            testosterone

                                                           Slide 19.


Neurons of the hypothalamus synthesize luteinizing hormone-releasing hormone
(LHRH). These cell bodies send axons to the median eminence, where LHRH is released
from the nerve terminals and is transported through vessels of the portal system. Upon
reaching the anterior pituitary, LHRH stimulates the release of LH, and to a lesser
degree FSH. Both gonadotropins are released into the general circulation and reach the
gonads

The gonads (testes and ovaries) have two major functions: steroid production (male:
testosterone; female: estrogen and progesterone) and gamete production (male: sperm;
female: ova). These functions are controlled by LH and FSH.

In males, it is primarily LH that stimulates testosterone production by Leydig cells,
while both LH and FSH participate in the spermatogenesis process that takes place in
the Sertoli cells-seminiferous tubules complex. In females, LH and FSH participate in
the synthesis and release of estrogen and progesterone by granulosa cells and cells of
the corpus luteum in the ovary, and stimulate the growth of the ovarian follicles and the
release of ova.

Steroids (testosterone, estrogen and progesterone) influence LHRH and gonadotropin
production through both a positive and a negative feedback, which maintains
appropriate levels of all the reproductive hormones.




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                               Alcohol and Endocrinology (Rivier)


   EFFECT OF ALCOHOL ON THE MALE REPRODUCTIVE SYSTEM
Alcohol is known to inhibit some aspects of the reproductive system. As in the case of
the HPA axis, this effect could be:

a) Exerted directly on:
    - The hypothalamus (LHRH synthesis)
    - The median eminance (LHRH release from nerve terminals)
    - The pituitary (blockade of LH/FSH release)
    - The gonads (blockade of steroid synthesis/release)

b) Exerted indirectly through activation of the HPA axis.

A. Effects of alcohol itself on components of the HPG axis.

Hypothalamus:
Alcohol inhibits LHRH synthesis/release. This is illustrated in Slide 20, which shows
that the proestrous release of LHRH in female rats were totally blocked by alcohol
injected at 8:00 am and 12:00 pm. LHRH was measured with a microdialysis probe
placed in the median eminence.

      LHRH (pg /sample )
         20   ve hi cle
               al cohol
          15   (3 g/kg, i p)

          10                                     Slide 20. Representative data from one rat
                                                 injected with alcohol. **, P<0.0.1 vs.
           5                                     vehicle.
           0
           1000 1200 1400 1600 1800
              time of day (proestrus)

Pituitary:
Alcohol decreases plasma LH levels. This is illustrated in studies carried out in
castrated rats, chosen as a model because they have elevated baseline LH
concentrations.




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                                        Alcohol and Endocrinology (Rivier)


       ng LH/ml
         4 ve hi cle
                    al cohol (3 g/kg, i p)
            3
                                                         Slide 21. Each point represents the mean
            2
                                                         + SEM of 4-5 rats. **, P<0.0.1 vs. vehicle.
            1

            0
                0        30      60    90     120
                              time (min)
As most investigators have failed to detect effects of alcohol on LHRH receptors, the
effect of alcohol on LH release is probably primarily due to blunted LHRH secretion.

    ng tes tosterone/m l
        4 ve hi cle
                al cohol (3 g/kg, i g)
        3
                                                         Slide 22. Each point represents the mean
        2                                                + SEM of 5 rats. **, P<0.01 vs. vehicle.
        1

        0
            0        30 60 90 120 150 180
                        time (min)

Testes:
Alcohol also significantly decreases testosterone release, as illustrated in Slide 22. There
are probably several causes for this decline. First, it is undoubtedly due at least in part to
reduced LH levels. In addition, alcohol may be able to alter the number and types of
sugar molecules present in the LH molecule, which decreases its biological activity on the
testes. Alcohol also acts directly on steroidogenic pathway in the testis, thereby inhibiting
the synthesis/release of this steroid. This may be due to the altered production of
intratesticular compounds that influence steroidogenesis and/or to inhibition of the
steroidogenic enzymes necessary for testosterone production. For example, we recently
reported that the injection of alcohol (4.5 g/kg) into the stomach, which results in the
presence of the drug in the blood stream, significantly decreased levels of proteins in
Leydig cells, that are important for testosterone synthesis (Slide 23).




                                                       22
                           Alcohol and Endocrinology (Rivier)


 StAR/Actin (% control)        PBR/Actin (% control)          P450scc/Actin (% control)
   160                          200                           250
   140                          180
                                160                           200
   120
                                140
   100
                                120                           150
    80                          100
    60                           80                           100
                                 60
    40
                                 40                             50
    20
                                 20
     0                            0                              0
         0   10 45 12 24 48           0   10 45  12 24 48            0 10 45  12 24 48
             min time h                   min time   h                 min time h

Slide 23.
However, we also found that we could modify the activity of these Leydig cells by
injecting alcohol into the brain, at doses that did not reach the periphery (Slide 24).
These results demonstrate that alcohol does not need to reach the testes to inhibit T
release. Our current hypothesis is that there is a neural pathway between the brain and
the testes that acutely and rapidly regulates Leydig cell activity in response to stress-
related signals in the brain.




Slide 24. Effect of injection of the vehicle
( ) or alcohol ( , 5 g) into the lateral
brain ventricle 15 min before stimulation
of T release by hCG (1.0 U/kg). Each
point represents the mean + SEM of 6 rats.
**, P < 0.01.




Collectively, these results indicate that alcohol can act at several sites to modify sex
steroids synthesis and release:

                                               23
                           Alcohol and Endocrinology (Rivier)



i. On hypothalamic LHRH neurons
ii. Directly on Leydig cells (when the drug is present in the blood stream)
iii. At least in males, on specific regions of the brain that respond to stress signals such
     as catecholamines or CRF

The importance of each of these mechanisms my depend on the amount of alcohol
ingested and/or the time frame over which the drug is present.

B. Effects of alcohol exerted through the HPA axis.
As we have seen, stressors such as alcohol activate the HPA axis, which results in
increased CRF synthesis in and release from the hypothalamus, and elevated circulating
levels of ACTH and glucocorticoids. Stressors, particulary those present for prolonged
periods of time, are also known to suppress various aspects of reproductive functions.
These include decreased sex steroid production, disrupted estrus/menstrual cycles,
impaired libido, delayed onset of puberty and impaired spermatogenesis.




Stress causes changes that are meant to help the survival of the individual and the
species. In the short term, these include mobilizing resources that are of immediate help
for the animal’s ability to fight or run (for example mobilization of sugars and fat
reserves); in the long term, these changes lead to the inhibition of biologically costly
behaviors and vegetative functions such as feeding/food processing, reproduction and
growth. Thus stress-induced suppression of reproductive functions can be viewed as an
adaptative response to conserve energy during hardship.




                                             24
                           Alcohol and Endocrinology (Rivier)




                                                       Slide 25. Some of the mechanisms
                                                       through which hormones of the
                                                       HPA axis inhibit the HPG axis.




Slide 25 illustrates what we currently understand of some of the mechanisms through
which hormones of the HPA axis inhibit the HPG axis. These include:

• At the hypothalamic level:
       - CRF-mediated inhibition of GnRH synthesis and release
       - CRF-stimulated opiate release, which in turn inhibits GnRH synthesis and
         release

• At the pituitary level:
       - Glucocorticoid-induced inhibition of LH release, in part due to interference
         with GnRH-induced stimulation of gonadotrophs activity

• At the gonadal level:
       - Glucocorticoid-induced inhibition of steroidogenesis through interference with
         specific enzymes that lead to sex steroid synthesis

Collectively, these results indicate that alcohol can inhibit the activity of the HPG axis
through a variety of distinct mechanisms that may involve direct effects of the drug
itself on components of the HPG axis, as well as effects exerted through hormones of
the HPA axis.

References

S. Rivest and C. Rivier. The role of corticotropin-releasing factor and interleukin-1 in the
regulation of neurons controling reproductive functions. Endocr Rev 16:177-199, 1995


                                             25
                          Alcohol and Endocrinology (Rivier)



K. Ogilvie and C. Rivier. Effect of alcohol on the proestrous surge of LH and the
activation of LHRH neurons in the female rat. J Neurosci 17: 595-2604, 1997.

M.E. Emanuele, J. Tentler, N.V. Emanuele and M.R. Kelley. In vivo effect of acute EtOH
on rat alpha and beta luteinizing hormone gene expression. Alcohol 8: 354-348, 1991.

N. LaPaglia, J. Steiner, L. Kirsteins, M.A. Emanuele and N. Emanuele. The impact of
acute ethanol on reproductive hormone synthesis, processing and secretion in female
rats at proestrus. Alcohol: Clin Exper Res 21: 1567-1572, 1997.

M.A. Emanuele and V.N. Emanuele. Alcohol’s effects on male reproduction. Alcohol
health and Research World 22: 195-201, 1998.

C. Rivier. Inhibitory effect of neurogenic and immune stressors on testosterone
secretion in rats. NeuroImmunoModulation 10:17-29, 2002.

H. Dobson, S. Ghuman, S. Prabhakar and R. Smith. A conceptual model of the influence
of stress on female reproduction. Reproduction 125: 151-163, 2003

D. Selvage, S. Lee, L. Parsons, D. Seo and C. Rivier. A hypothalamic-testicular neural
pathway is influenced by brain catecholamines, but not testicular blood flow.
Endocrinology 145:1750-1759, 2004.

D.J. Selvage, D.B. Hales and C.L. Rivier. Comparison between the influence of the
systemic and central injection of alcohol on Leydig cell activity. Alcoholism: Clin Exper
Res 28:480-488, 2004.




                                           26

				
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